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This paper by Ooms and colleagues studies the effect of sleep deprivation in humans on cerebrospinal fluid (CSF) Aβ40, Aβ42, tau, p-tau, and total protein in middle-aged individuals with lumbar catheters.

It is found that CSF Aβ42 decreased in those who had normal sleep by the morning, reflecting when Aβ was being produced in the brain during sleep; whereas it did not decrease in those who were sleep deprived. There was no change in tau, p-tau, or Aβ40. This is interesting and is very similar to results we observed in APP transgenic mice (Kang et al., 2009). This supports that Aβ is dynamically regulated by the sleep-wake cycle. There would be several things to follow up on in future studies. It is not clear why Aβ40 did not also change with sleep deprivation in this study. Since the research subjects who were not sleep deprived did not have lumbar catheter sampling between 10 p.m. and 9 a.m., whereas those who were sleep-deprived did, one wonders if this difference in sampling affected the results in some way. The authors controlled for this by measuring total protein, but this should be reassessed in future studies. It might also be useful to sample CSF just in the AM (without a lumbar catheter) to reflect the overnight period of Aβ production. With a lumbar catheter in place, this probably affects the group that was attempting to get normal sleep. Overall, however, the authors should be applauded for going out of their way to do a very involved study that strongly suggests that sleep deprivation in humans results in acute elevation in CSF Aβ42 and supports the hypothesis that chronic sleep deprivation could lead to an acceleration of Aβ deposition.

This well-designed and -analyzed study fills an important gap in our understanding of the association between sleep and CNS amyloid β (Aβ) dynamics in humans. There is a growing body of epidemiological evidence relating sleep disturbance to cognition and dementia in older persons. One hypothesis suggests that sleep deprivation/disruption may affect the production/clearance of Aβ. Prior experimental work had indicated that to be the case in rodents. One previous study in humans had looked at the temporal dynamics of CSF Aβ, but this was an observational study, limiting the ability to draw conclusions about causality. In contrast, this work by Ooms and colleagues used a randomized interventional design, providing strong evidence that at least in healthy middle-aged individuals, perturbations in sleep can, in principle, attenuate the normal nocturnal decline in CSF Aβ levels. Particular strengths include its randomized interventional design, careful and repeated serial measurements of CSF Aβ within the same individuals, and direct quantification of sleep.

Much work remains to be done in this area. Whether this experimental effect seen in healthy middle-aged individuals is sufficiently large to be clinically significant vis-à-vis later-life Alzheimer's disease risk is unknown. Moreover, total sleep deprivation is unusual in the real world, and it is unclear whether partial sleep deprivation and sleep fragmentation, which are much more common, would have the same effects. In addition, whether there is an important effect of circadian disruption (which is commonly seen in the context of shift work) on amyloid dynamics remains uncertain.

Notwithstanding the need for additional work, this study by Ooms and colleagues bridges an important gap between prior experimental studies in rodent models and human epidemiological studies, and will provide a good foundation to gauge the importance of sleep and amyloid dynamics to clinical Alzheimer's disease risk.

David Holtzman and Andrew Lim raise important points for future studies on this topic. Some further thoughts for those who would like to engage in a follow-up study:

Despite the overnight stay in a hospital-like environment (clinical research lab) and the presence of the spinal catheter, the 13 subjects who were allowed to sleep normally achieved sufficient sleep (according to our observatinos, and as seen on EEG). Nonetheless, the EEG revealed differences in the time spent in deep sleep (S3), which may have been influenced by the research setting.

In a future study, our advice would be to withhold nightly sampling in the sleep-deprived group. We performed these samples because we wanted to pinpoint the timing of changes in Aβ overnight. Our study clearly showed that there were no relevant Aβ dynamics between midnight and morning. Therefore, future studies could keep the sampling scheme exactly the same in the two groups (normal sleep vs. sleep deprivation).

We would also advise to extend the morning sampling until noon. We stopped sampling at 10 a.m., but also saw the largest decline (in the normal sleep group) at 10 a.m. It would be interesting to know if Aβ declines even further later in the morning (i.e., the maximum decline could be at 11 a.m.).